MOUSE MODEL FOR BLOOM SYNDROME & TUMOR SUPPRESSOR GENES

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DESCRIPTION (Applicant's Description): The long-term objective of this grant is to study the underlying mechanisms that govern somatic recombination and somatic loss of heterozygosity (LOH) during cancer development and to develop mouse models with increased rates of somatic LOH as tools to identify novel tumor suppressor genes. Somatic LOH plays an important role in cancer development. It is largely responsible for the second event that is required for the complete loss of function of a tumor suppressor gene. Thus the understanding of these mechanisms will be important for the advancement of our knowledge on the initiation and/or progression of cancer and hence may lead to better diagnosis, prevention and treatments of this disease. In mammalian cells, there exist two major pathways that can lead to LOH: chromosome mis- segregation, and recombination-based (segmental) LOH, with the segmental type of LOH being the predominant type in human cancer. The human Bloom syndrome provides a unique model to study this important process. Bloom syndrome is a cancer-prone disorder due to loss of function mutations in a gene encoding a RecQ DNA helicase. Studies in E. coli and in yeast suggest that the RecQ helicase is an antagonist of recombination. Both Bloom syndrome patients and the corresponding yeast mutants display a hyper-recombination phenotype. It is therefore hypothesized that Bloom syndrome patients are predisposed to cancer due to an elevated segmental LOH process that accelerates the uncovering of phenotypic effects of otherwise silent single mutations in tumor suppressor genes. in addition, it has been reported very recently that the Rothmund- Thomson syndrome, another cancer prone syndrome, is caused by mutations in RecQ4, another gene coding for a RecQ DNA helicase. Thus, mouse models of these syndromes should provide excellent tools to study segmental LOH and may also be useful for gene identification in a genetic screen. The specific aims of this grant are: to generate mouse models of the human Bloom syndrome and Rothmund-Thomson syndrome; to study effects of mutations in Blm and RecQ4 on somatic recombination and LOH; to examine the effects of mutations in Blm and RecQ4 on tumor susceptibility in mice; and to evaluate the usefulness of these mouse models as tools to increase the ease of identifying novel tumor suppressor genes in the context of somatic insertion- tagged mutagenesis.